Prednicarbate versus conventional topical glucocorticoids: pharmacodynamic characterization in vitro.
OBJECTIVE
Pharmacodynamic characterization of topical glucocorticoids as prednicarbate (PC), its metabolites prednisolone 17-ethylcarbonate (PEC) and prednisolone (PD), betamethasone 17-valerate (BMV), betamethasone (BM) and desoximetasone (DM) by evaluating their effects on epidermal and dermal cells. Synopsis of pharmacokinetic and pharmacodynamic studies, possibly explaining the improved benefit-risk ratio of prednicarbate.


METHODS
Isolated foreskin keratinocytes were used to investigate the influence on epidermal inflammatory processes, dermal fibroblasts of the same origin to study antiproliferative activities of glucocorticoids. Interleukins were measured by ELISA-assay, the influence on II-1 alpha-production also on mRNA-level by RNAse protection assay. Proliferation was assessed by 3H thymidine incorporation and biodegradation by HPLC/UV-absorption. Cell viability was controlled by MTT assay.


RESULTS
In keratinocytes, inflammation was induced by TNF alpha, resulting in an increased II-1 alpha synthesis. This cytokine was particularly suppressed by PC and BMV, whereas PEC, PD, DM and BM were less potent (p < or = 0.05). Since, however, the double ester PC is rapidly degraded in keratinocytes, a RNAse-protection assay of II-1 alpha mRNA was performed allowing short incubation times and thus minimizing biodegradation effects. In agreement with the previous experiment, the antiinflammatory potency of native PC was confirmed. In fibroblasts, II-1 alpha and II-6 synthesis indicate proliferation and inflammation respectively. Whereas PC inhibited II-1 alpha and II-6 production in fibroblasts to a minor extent only, it was strongly reduced by the conventional glucocorticoids and PEC (p < or = 0.05). The minor unwanted effect of PC on fibroblasts was also reflected by its low influence on cell proliferation as assayed by 3H thymidine incorporation. More pronounced antiproliferative features were observed with BM, PEC and especially BMV.


CONCLUSIONS
Correlating antiphlogistic effects in keratinocytes (suppression of II-1 alpha) with antiproliferative effects in fibroblasts (suppression of II-1 alpha and II-6), the improved benefit-risk ratio of PC compared to conventional glucocorticoids does not result only from distinct drug metabolism in the skin but also from a specific influence on the cytokine network.
Lange
K
K
Institut für Pharmazie II, Abteilung Pharmakologie und Toxikologie Freie Universität Berlin.
Gysler
A
A
Bader
M
M
Kleuser
B
B
Korting
H C
HC
Schäfer-Korting
M
M
D000287:Administration, Topical; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001624:Betamethasone Valerate / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003899:Desoximetasone / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D015603:Keratinocytes / Q000187:drug effects; D011239:Prednisolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D012867:Skin / Q000187:drug effects*; D013936:Thymidine / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; C085709:prednisolone 17-ethylcarbonate; D003899:Desoximetasone; D001624:Betamethasone Valerate; D011239:Prednisolone; C035287:prednicarbate; D013936:Thymidine